ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser)

gnomAD frequency: 0.00004  dbSNP: rs200804638
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181226 SCV000233505 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing The P629S variant in the DSG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P629S variant is observed in 2/33,576 (0.01%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The P629S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P629S as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000642309 SCV000763978 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 629 of the DSG2 protein (p.Pro629Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 199813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000223710 SCV000919282 uncertain significance not specified 2018-11-05 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1885C>T (p.Pro629Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246854 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1885C>T, has been reported in the literature in one individual affected with Alcoholic Cardiomyopathy (Ware_2018), together with the pathogenic TTN .43144_43147delCTGG (p.Leu14382ValfsTer2). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001187863 SCV001354765 uncertain significance Cardiomyopathy 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 629 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having arrhythmogenic cardiomyopathy (PMID: 33652588) and in an individual affected with dilated cardiomyopathy, who also carried a truncation variant in the TTN gene (PMID: 32826072). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003372640 SCV004096025 uncertain significance Cardiovascular phenotype 2023-08-29 criteria provided, single submitter clinical testing The p.P629S variant (also known as c.1885C>T), located in coding exon 13 of the DSG2 gene, results from a C to T substitution at nucleotide position 1885. The proline at codon 629 is replaced by serine, an amino acid with similar properties. This variant co-occurred with a frameshift variant in the TTN gene in an individual with alcohol-induced cardiomyopathy, and has also been detected in an individual from a dilated cardiomyopathy cohort and an individual with possible arrhythmogenic right ventricular cardiomyopathy; however, details were limited (Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; Vallverd&uacute;-Prats M et al. J Pers Med, 2021 Feb;11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV003996619 SCV004819584 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 629 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having arrhythmogenic cardiomyopathy (PMID: 33652588) and in an individual affected with dilated cardiomyopathy, who also carried a truncation variant in the TTN gene (PMID: 32826072). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000642309 SCV005398678 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD 10; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive inheritance has been reported in severe DCM patients (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Patients with variants causing ARVC have been reported with a penetrance of 58-75% (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Two other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Two alternative changes to a threonine and a glutamine have each been reported as VUS in individuals with dilated cardiomyopathy and hypertrophic cardiomyopathy, respectively (PMID: 30847666). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been described as a VUS in multiple individuals with cardiomyopathy or arrhythmogenic right ventricular dysplasia (ClinVar, PMID: 33652588). It has also been reported in one alcoholic cardiomyopathy individual without classification (PMID: 29773157). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223710 SCV000280083 uncertain significance not specified 2014-03-20 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we would categorize this as a variant of unknown significance (VUS). This variant has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a non-conservative amino acid substitution in which a non-polar Proline is replaced by a neutral, polar Serine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Only one missense variant at a nearby residue has been reported in HGMD in association with ARVC, which may or may not support the functional importance of this region of the protein: Gly638Arg (HGMD professional version as of January 17, 2014). The variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variant at codon 629 listed in 1000 genomes (as of March 20, 2014). The Pro629Ser variant is listed in dbSNP.

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